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Bouvet M, Dubois-Deruy E, Turkieh A, et al. Desmin aggrephagy in rat and human ischemic heart failure through PKCζ and GSK3β as upstream signaling pathways. Cell Death Discov. 2021;7(1):153doi: 10.1038/s41420-021-00549-2.
Bouvet, M., Dubois-Deruy, E., Turkieh, A., Mulder, P., Peugnet, V., Chwastyniak, M., Beseme, O., Dechaumes, A., Amouyel, P., Richard, V., Lamblin, N., & Pinet, F. (2021). Desmin aggrephagy in rat and human ischemic heart failure through PKCζ and GSK3β as upstream signaling pathways. Cell death discovery, 7(1), 153. https://doi.org/10.1038/s41420-021-00549-2
Bouvet, Marion, et al. "Desmin aggrephagy in rat and human ischemic heart failure through PKCζ and GSK3β as upstream signaling pathways." Cell death discovery vol. 7,1 (2021): 153. doi: https://doi.org/10.1038/s41420-021-00549-2
Bouvet M, Dubois-Deruy E, Turkieh A, Mulder P, Peugnet V, Chwastyniak M, Beseme O, Dechaumes A, Amouyel P, Richard V, Lamblin N, Pinet F. Desmin aggrephagy in rat and human ischemic heart failure through PKCζ and GSK3β as upstream signaling pathways. Cell Death Discov. 2021 Jun 26;7(1):153. doi: 10.1038/s41420-021-00549-2. PMID: 34226534; PMCID: PMC8257599.
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Cell Death Discov. 2021 Jun 26;7(1):153. doi: 10.1038/s41420-021-00549-2.

Desmin aggrephagy in rat and human ischemic heart failure through PKCζ and GSK3β as upstream signaling pathways.

Cell death discovery

Marion Bouvet, Emilie Dubois-Deruy, Annie Turkieh, Paul Mulder, Victoriane Peugnet, Maggy Chwastyniak, Olivia Beseme, Arthur Dechaumes, Philippe Amouyel, Vincent Richard, Nicolas Lamblin, Florence Pinet

Affiliations

  1. INSERM, Univ. Lille, CHU Lille, Institut Pasteur de Lille, U1167 - RID-AGE - Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement, F-59000, Lille, France.
  2. Normandie Univ, UNIROUEN, Inserm U1096, FHU-REMOD-VHF, 76000, Rouen, France.
  3. INSERM, Univ. Lille, CHU Lille, Institut Pasteur de Lille, U1167 - RID-AGE - Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement, F-59000, Lille, France. [email protected].

PMID: 34226534 PMCID: PMC8257599 DOI: 10.1038/s41420-021-00549-2

Abstract

Post-translational modifications of cardiac proteins could participate to left contractile dysfunction resulting in heart failure. Using a rat model of ischemic heart failure, we showed an accumulation of phosphorylated desmin leading to toxic aggregates in cardiomyocytes, but the cellular mechanisms are unknown. The same rat model was used to decipher the kinases involved in desmin phosphorylation and the proteolytic systems present in rat and human failing hearts. We used primary cultures of neonate rat cardiomyocytes for testing specific inhibitors of kinases and for characterizing the autophagic processes able to clear desmin aggregates. We found a significant increase of active PKCζ, no modulation of ubitiquitin-proteasome system, a defect in macroautophagy, and an activation of chaperone-mediated autophagy in heart failure rats. We validated in vitro that PKCζ inhibition induced a significant decrease of GSK3β and of soluble desmin. In vitro activation of ubiquitination of proteins and of chaperone-mediated autophagy is able to decrease soluble and insoluble forms of desmin in cardiomyocytes. These data demonstrate a novel signaling pathway implicating activation of PKCζ in desmin phosphorylation associated with a defect of proteolytic systems in ischemic heart failure, leading to desmin aggrephagy. Our in vitro data demonstrated that ubiquitination of proteins and chaperone-mediated autophagy are required for eliminating desmin aggregates with the contribution of its chaperone protein, α-crystallin Β-chain. Modulation of the kinases involved under pathological conditions may help preserving desmin intermediate filaments structure and thus protect the structural integrity of contractile apparatus of cardiomyocytes by limiting desmin aggregates formation.

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